Trends in Neurosciences
ReviewSpace, time and dopamine
Introduction
The contributions of dopamine to movement and learning are frequently viewed dichotomously, with motor-activating effects associated with relatively constant dopamine levels, in contrast to the phasic concentration spikes associated with positive reinforcement. The anatomical arrangement of dopaminergic synapses might support the hypothesis that dopamine has spatially localized actions at specific corticostriatal synapses. An extrasynaptic location of dopamine receptors has been used to support the hypothesis of a nonselective signalling mode based on volume transmission. We argue, to the contrary, that both motor-activating and reinforcement functions are related to phasic dopamine signalling, that biophysical considerations make spatially selective actions of dopamine unlikely, and that the volume-transmission mode can be synaptically specific if combined by temporal coincidence with glutamatergic activity.
Section snippets
Individual dopaminergic synapses on spines might not account for selectivity
The anatomical arrangement of dopaminergic synapses seems to suggest a spatially localized action of dopamine. The synapses are small in area, often visible on only one 60-nm section in a series. They end on spiny output neurons in the striatum, mainly on the necks of spines that also receive an asymmetric excitatory synapse on their head 1, 2. The arrangement of an asymmetric synapse on the spine head and a dopaminergic synapse at its base has given rise to the opinion that the individual
A smaller than expected fraction of spines receive dopaminergic synapses
Although examination of an individual dendrite suggests that a majority of spines receive dopaminergic synapses [2], quantitative considerations (Table 1) indicate that only a small fraction of spines has them. These considerations are derived from the density of dopaminergic synapses obtained using the density of all synapses from unbiased stereology [3] and the proportion of synapses that seem to be dopaminergic according to their staining by 5-hydroxydopamine in serial electromicograph
Spines without dopaminergic synapses might still receive dopamine signals
To understand the functional implications of the relatively sparse distribution of dopaminergic synapses, it is important to know whether the released dopamine is confined in the synaptic cleft. Alternatively, the release site might be the centre of a sphere of influence, the extent of which might be regulated by, for example, the diffusion distance of effective concentrations of dopamine or the distance between the dopamine release sites and their targets. Drugs of abuse that modify reuptake
Biophysical considerations suggest an overlapping influence of neighbouring synapses
The spatial selectivity of the action of dopamine depends on the degree to which the individual microspheres of influence of each dopamine release site overlap. Quantitatively, the region of influence of dopamine in the extracellular space around a single release site is determined by the interaction between diffusion and reuptake. Figure 2c illustrates the predicted spatiotemporal distribution of dopamine after its release from a single release site 12, 13. Because of the close packing of
The firing of a single dopaminergic neuron probably produces a heterogeneous concentration distribution of dopamine
What is the spatial distribution of dopamine when a single dopaminergic neuron fires? The answer to this question is crucial in determining the degree of selectivity that is possible for the dopaminergic inputs. For example, does a dopamine cell influence only the dendritic spines on which it terminates or does its influence spread more widely than that? The way the individual microspheres around each synapse interact depends on the degree of divergence of individual axons and the volume in
Resting firing patterns of dopaminergic cell populations produce a more homogenous concentration distribution
Electrophysiological recordings from dopaminergic cells in the substantia nigra that were identified antidromically showed a range of firing rates in anaesthetized animals. Cells initially identified included silent neurons, slowly firing neurons and neurons firing in short bursts 17, 18, 19. Dopaminergic cells are not silent ‘at rest’ [20]. In the resting state, asynchronous activity among a population of dopaminergic cells will produce a uniform distribution of dopamine by equilibration of
Salient events produce phasic and coordinated firing patterns of dopaminergic neurons
The homogeneous concentration distribution applies to the tonic resting activity of dopaminergic neurons. What of the firing patterns that occur during behaviour? In the past decade, recordings from dopaminergic cells in awake animals, which can move and respond to external cues, have begun to suggest an intriguing role for these cells in animal behaviour.
Studies in monkeys initiated by Schultz and colleagues have altered our opinion of the involvement of dopaminergic cells in behaviour by
Dopamine functions diffusely in space but selectively in time
Although dopamine might be diffuse in space, its action in response to salient stimuli is not diffuse in time. Dopamine diffusion and reuptake occur rapidly, relative to a behavioural timeframe, so that firing of a single dopaminergic cell produces a brief, pulsatile increase in the concentration of dopamine. Around each synaptic contact, this dopamine ‘pulse’ (Figure 2c) is predicted to remain significantly elevated for no more than 50 ms and to have a sphere of influence of 7 μm [7]. Such
Timed pulses of dopamine determine its postsynaptic actions
The postsynaptic transduction of the dopamine signal, whether the concentration is in a steady state, transiently increased or transiently decreased, depends on the dopamine receptors on the postsynaptic cells. The steady-state concentration of dopamine seems to be sufficient to activate both D1 and D2 subtypes of dopamine receptor on postsynaptic membranes, because locally applied antagonists of either receptor subtype produce physiological effects. Two broad classes of postsynaptic effects
Reward-related dopamine release also occurs in the human brain
Positron-emission tomography imaging of dopamine receptor occupancy has provided evidence of dopamine release in the human striatum associated with the subjective effects of cocaine 32, 33, 34 and during active participation in computer games [35]. This evidence supports the hypothesis that the same – or at least a similar – involvement in rewarded behaviour might be expected from human dopaminergic neurons.
The consequences of a lack of dopamine might reflect the loss of phasic reward signalling, leading to extinction
Any description of the actions of dopamine must also account for the consequences of its lack – for example, in Parkinson's disease. This part of the story is more controversial: some investigators interpret the loss of dopamine as a negative value of reinforcement [36], whereas others consider tonic levels of dopamine crucial for movement [37]. However, the ‘reward’ hypothesis includes an explanation that might lead to dramatic changes in the way Parkinsonian patients are managed. If the only
Concluding remarks
Taking in consideration quantitative aspects of the neuroanatomy of dopaminergic synapses in the striatum, we are led to the conclusion that dopamine must act as a volume transmitter. Effects of dopamine are limited to specific synapses by its activity-dependent actions rather than spatially limited release. The function of phasic dopaminergic activity in the striatum is to mark the salient time points in the behavioural sequences. By this mechanism, dopamine strengthens the appropriate
Acknowledgements
The ideas presented in this review were generated during many conversations. We are particularly grateful to Prof. R.G.M. Morris for many helpful suggestions on early drafts of the manuscript, and to Prof. S.B. Dunnett for giving us the reason to think about the consequences of the anatomical results for the Handbook of Chemical Neuroanatomy [41].
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